Disulfiram and metal salt staggered oral dosing regimen and staggered-release oral unit dosage forms

Abstract

This application relates to methods and compositions for the administration of disulfiram (DSF) and heavy metals zinc and copper for the treatment and prevention of medical conditions, such as cancer. DSF and copper as well as DSF and zinc form active complexes that have been shown to be effective in the treatment of cancers. However, as described herein, DSF is incompatible with either copper or zinc for simultaneous oral administration. Included herein are improved methods and oral dosage forms comprising DSF and copper and DSF and zinc in fixed dose combinations that are configured to temporally stagger release of either DSF and copper or DSF and zinc after ingestion.

What is claimed is: 
     
       1. A method of treating glioblastoma, pancreatic, or colorectal cancer, comprising:
 administering to a subject with glioblastoma, pancreatic, or colorectal cancer an oral dosage form configured to temporally stagger release of disulfiram (“DSF”) and copper after ingestion, 
 wherein the copper is released following the release of DSF, is formulated to be released greater than 30 minutes after the release of DSF, and is in the form of copper gluconate or copper glycinate. 
 
     
     
       2. The method of  claim 1 , wherein the copper is in the form of copper gluconate. 
     
     
       3. The method of  claim 1 , wherein the copper is formulated to be released 1 to 3 hours after release of DSF. 
     
     
       4. The method of  claim 1 , wherein the DSF is upon exposure to a pH greater than 5.0 in the digestive system of the subject. 
     
     
       5. The method of  claim 4 , wherein the copper is released upon exposure to a pH greater than 7.0 in the digestive system of the subject. 
     
     
       6. The method of  claim 1 , wherein the copper is coated with an enteric coating. 
     
     
       7. The method of  claim 1 , wherein the oral dosage form further comprises at least one pharmaceutical excipient selected from the group consisting of a polymeric material, a hydrophobic matrix, a hydrophilic matrix and a disintegrant. 
     
     
       8. The method of  claim 1 , wherein the oral dosage form comprises a capsule containing at least one DSF minitablet and at least one copper minitablet. 
     
     
       9. The method of  claim 1 , further comprising:
 administering an effective amount of at least one additional anti-cancer agent prior to, concurrently with, or after the administration of the oral dosage form of DSF and copper. 
 
     
     
       10. The method of  claim 1 , wherein the oral dosage form further comprises an additional anti-cancer agent. 
     
     
       11. The method of  claim 9 , wherein the additional anti-cancer agent is selected from the group consisting of radiation, chemotherapeutic, a targeted anti-cancer agent, an antibody, a small molecule inhibitor, a chemokine, a nucleic acid, an immunomodulator, a hormonal agent and combinations thereof. 
     
     
       12. The method of  claim 11 , wherein the additional anti-cancer agent is temozolomide. 
     
     
       13. The method of  claim 1 , wherein the administration results in reduced tumor burden in the subject. 
     
     
       14. The method of  claim 1 , wherein administration of DSF and copper results in increased progression-free survival and/or overall survival of the subject. 
     
     
       15. The method of  claim 8 , wherein the at least one DSF minitablet comprises 10 mg to 1.0 g of DSF. 
     
     
       16. The method of  claim 8 , wherein the at least one copper minitablet comprises 0.1 mg to 30 mg of copper gluconate. 
     
     
       17. The method of  claim 1 , wherein the oral dosage is a capsule. 
     
     
       18. The method of  claim 6 , wherein the enteric coating is a pH-sensitive coating.